Placental hypoxia plays an important role in preeclampsia, a severe form of pregnancy-induced hypertension that afflicts ~5-8% of pregnant women. Preeclampsia has long been associated with thrombotic complications that can be life-threatening. To date, the mechanism that connects placental hypoxia and preeclampsia-associated thrombotic disorders remains poorly understood. Our latest studies indicate that placental hypoxia may up-regulate high mobility group box-1 (HMGB1) protein expression in trophoblasts, which in turn causes endothelial damage and enhances blood coagulation, thereby contributing to thrombosis. In this proposal, we plan to conduct studies to define the role of HMGB1 from hypoxic trophoblasts in preeclampsia-associated thrombotic disease. In Aim 1, we plan to determine the role of HMGB1 from hypoxic trophoblasts in promoting endothelial microparticle production and blood coagulation in cell- and protein-based studies. In Aim 2, we plan to examine the role of HMGB1 in promoting endothelial microparticle production and blood coagulation in mouse models. Our studies should help to understand how hypoxia-induced changes in trophoblasts lead to maternal endothelial dysfunction and enhanced blood coagulation in patients with preeclampsia.